Systems, apparatuses, and methods for delivery of pulsed electric field ablative energy to endocardial tissue

ABSTRACT

Systems, devices, and methods for electroporation ablation therapy are disclosed herein, including an inflatable member for positioning an ablation device within a pulmonary vein ostium. An apparatus can include first and second shafts moveable relative to one another, first and second electrodes configured to generate an electric field for ablating tissue, and an inflatable member disposed between the first and second electrodes. In some embodiments, the inflatable member is configured to transition from an undeployed configuration to a deployed configuration in response to movement of the first and second shafts. In some embodiments, the inflatable member in the deployed configuration can engage a wall of a pulmonary vein ostium and direct the electric field generated by the first and second electrodes toward the wall.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/734,214, filed on Sep. 20, 2018, the entire disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND

The generation of pulsed electric fields for tissue therapeutics hasmoved from the laboratory to clinical applications over the past twodecades, while the effects of brief pulses of high voltages and largeelectric fields on tissue have been investigated for the past fortyyears or more. Application of brief high DC voltages to tissue maygenerate locally high electric fields typically in the range of hundredsof volts per centimeter that disrupt cell membranes by generating poresin the cell membrane. While the precise mechanism of thiselectrically-driven pore generation or electroporation continues to bestudied, it is thought that the application of relatively brief andlarge electric fields generates instabilities in the lipid bilayers incell membranes, causing the occurrence of a distribution of local gapsor pores in the cell membrane. This electroporation may be irreversibleif the applied electric field at the membrane is larger than a thresholdvalue such that the pores do not close and remain open, therebypermitting exchange of biomolecular material across the membrane leadingto necrosis and/or apoptosis (cell death). Subsequently, the surroundingtissue may heal naturally.

While pulsed DC voltages may drive electroporation under the rightcircumstances, there remains an unmet need for thin, flexible,atraumatic devices that effectively deliver high DC voltageelectroporation ablation therapy selectively to endocardial tissue inregions of interest while minimizing damage to healthy tissue.

BRIEF SUMMARY

Described here are systems, devices, and methods for ablating tissuethrough irreversible electroporation. In some embodiments, an apparatuscan include a first shaft having a longitudinal axis and defining alumen; a second shaft disposed within the lumen and having a distalportion that extends from a distal portion of the first shaft, thesecond shaft moveable along the longitudinal axis relative to the firstshaft; a first electrode coupled to the distal portion of the firstshaft; a second electrode coupled to the distal portion of the secondshaft, the first and second electrodes configured to generate anelectric field for ablating tissue; and an inflatable member disposedbetween the first and second electrodes, the inflatable memberconfigured to transition from an undeployed configuration to a deployedconfiguration in response to the second shaft being moved proximallyrelative to the first shaft, the inflatable member in the deployedconfiguration configured to engage a wall of a pulmonary vein ostium anddirect the electric field generated by the first and second electrodestoward the wall.

In some embodiments, an apparatus can include a shaft having alongitudinal axis and defining a lumen; an inflatable member disposednear a distal portion of the shaft, the inflatable member configured totransition between an undeployed configuration and a deployedconfiguration, the inflatable member including a wall having a proximalportion, a distal portion, and a middle portion disposed between theproximal and distal portions of the wall, the middle portion having aminimum thickness that is less than a thickness of the proximal anddistal portions of the wall; and first and second electrodes disposed onopposite sides of the inflatable member along the longitudinal axis, thefirst and second electrodes configured to generate an electric field forablating tissue.

In some embodiments, a system can include a signal generator configuredto generate a pulse waveform; an ablation device coupled to the signalgenerator, the ablation device including: first and second electrodesconfigured to receive the pulse waveform and generate an electric fieldfor ablation; and an inflatable member formed of an insulating materialand disposed between the first and second electrodes, the inflatablemember configured to transition between an undeployed configuration inwhich the inflatable member can be advanced to a pulmonary vein ostiumto a deployed configuration in which the inflatable member can engagewith a wall of the pulmonary vein ostium, the inflatable member in thedeployed configuration configured to direct the electric field towardthe wall.

In some embodiments, a method can include retracting an inner shaft ofan ablation device relative to an outer shaft of the ablation device,the inner shaft disposed within a lumen of the outer shaft;transitioning, in response to retracting the inner shaft relative to theouter shaft, an inflatable member of the ablation device from anundeployed configuration to a deployed configuration in which a sideportion of the inflatable member engages a wall of a pulmonary veinostium; and delivering, after the transitioning, a pulse waveform tofirst and second electrodes of the ablation device such that the firstand second electrodes generate an electric field for ablating the wallof the pulmonary vein ostium, the first and second electrodes disposedon opposite sides of the inflatable member.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of an electroporation system, according toembodiments.

FIG. 2A is a side view of an ablation device in an inflated state,according to embodiments.

FIG. 2B is a side view of an ablation device depicted in FIG. 2A in adeflated state, according to embodiments.

FIG. 3 is a cross-sectional side view of an ablation device disposed ina pulmonary vein, according to embodiments.

FIG. 4A is a cross-sectional side view of an ablation device disposed ina pulmonary vein, according to embodiments. FIG. 4B is a perspectiveview of an ablation zone associated with the ablation device depicted inFIG. 4A when disposed in a pulmonary vein, according to embodiments.

FIG. 5A is a cross-sectional side view of an ablation device disposed ina pulmonary vein, according to embodiments. FIG. 5B is a cross-sectionalside view of the ablation device depicted in FIG. 5A disposed in apulmonary vein.

FIG. 6A is a cross-sectional side view of an ablation device disposed ina pulmonary vein, according to embodiments. FIG. 6B is a cross-sectionalside view of an ablation zone of the ablation device depicted in FIG. 6Adisposed in a pulmonary vein.

FIG. 7 is a side view of an ablation device, according to embodiments.

FIG. 8 is a side view of an ablation device, according to embodiments.

FIG. 9 is a perspective view of an ablation device, according toembodiments.

FIG. 10 is a schematic side view of a portion of a wall of an inflatablemember of an ablation device, according to embodiments.

FIG. 11 is a schematic side view of a portion of a wall of an inflatablemember of an ablation device, according to embodiments.

FIGS. 12A and 12B are different views of an ablation device, accordingto embodiments.

FIG. 13 is a cross-sectional side view of the ablation device depictedin FIGS. 12A and 12B.

FIG. 14 is a cross-sectional side view of an ablation zone of theablation device depicted in FIGS. 12A and 12B.

FIG. 15 is an example waveform showing a sequence of voltage pulses witha pulse width defined for each pulse, according to embodiments.

FIG. 16 schematically illustrates a hierarchy of pulses showing pulsewidths, intervals between pulses, and groupings of pulses, according toembodiments.

FIG. 17 provides a schematic illustration of a nested hierarchy ofmonophasic pulses displaying different levels of nested hierarchy,according to embodiments.

FIG. 18 is a schematic illustration of a nested hierarchy of biphasicpulses displaying different levels of nested hierarchy, according toembodiments.

FIG. 19 illustrates schematically a time sequence of electrocardiogramsand cardiac pacing signals together with atrial and ventricularrefractory time periods and indicating a time window for irreversibleelectroporation ablation, according to embodiments.

FIGS. 20A-20B illustrates a method for tissue ablation, according toembodiments.

DETAILED DESCRIPTION

Described here are systems, devices, and methods for ablating tissuethrough irreversible electroporation. Generally, an apparatus fordelivering a pulse waveform to tissue may include a first catheter(e.g., shaft) defining a longitudinal axis. An expandable/inflatablemember may be coupled to a distal portion of the first catheter. A firstelectrode may be coupled to the distal portion of the first catheter andproximal to the inflatable member. A second catheter (e.g., shaft) ortubular lumen may be disposed within a lumen of the first catheter and achamber of the expandable/inflatable member where the second cathetermay be slidable relative to the first catheter. Theexpandable/inflatable member may be coupled to a distal end of thesecond catheter. A second electrode may be coupled to the distal portionof the second catheter and distal to the inflatable member. In someembodiments the second catheter, and in particular its distal portion,may be steerable linearly relative to the first catheter. Thus in someembodiments, the second electrode may be steerable relative to the firstelectrode. A proximal portion of the expandable/inflatable member may becoupled to the distal portion of the first catheter and a distal portionof the expandable/inflatable member may be coupled to the distal portionof the second catheter or tubular lumen. The second catheter may have alumen diameter sufficient to pass a guidewire through the lumen. Theguidewire may provide mechanical support for the first and secondcatheters. In some embodiments, the first electrode may comprise a firstset of electrodes and the second electrode may comprise a second set ofelectrodes.

Generally, a system for delivering a pulse waveform to tissue mayinclude a signal generator configured for generating a pulse waveformand an ablation device coupled to the signal generator and configured toreceive the pulse waveform. The ablation device may include anexpandable/inflatable member (e.g., a balloon) coupled to a distalportion of a first catheter for delivering energy to ablate tissue byirreversible electroporation. One or more electrodes may be formedproximal to the expandable/inflatable member on a surface of the firstcatheter.

In some embodiments, a system may include a signal generator configuredfor generating a pulse waveform. An ablation device may be coupled tothe signal generator and configured for receiving the pulse waveform.The ablation device may include a handle configured to move the secondelectrode relative to the first electrode. The system may include acardiac stimulator for generation of pacing signals and for delivery ofpulse waveforms in synchrony with the pacing signal. In someembodiments, one or more of the electrodes may have an insulatedelectrical lead associated therewith, the insulated electrical leadconfigured for sustaining a voltage potential of at least about 700 Vwithout dielectric breakdown of its corresponding insulation, theinsulated electrical lead disposed in a lumen of the catheter. In someembodiments, one or more of the electrodes may be independentlyaddressable.

In some embodiments, a pulse waveform may include a first level of ahierarchy of the pulse waveform in the form of a first set of pulses,each pulse having a pulse time duration, a first time intervalseparating successive pulses. A second level of the hierarchy of thepulse waveform includes a plurality of first sets of pulses as a secondset of pulses, a second time interval separating successive first setsof pulses, the second time interval being at least three times theduration of the first time interval. A third level of the hierarchy ofthe pulse waveform includes a plurality of second sets of pulses as athird set of pulses, a third time interval separating successive secondsets of pulses, the third time interval being at least thirty times theduration of the second level time interval. In some of theseembodiments, the pulse waveform includes a fourth level of the hierarchyof the pulse waveform includes a plurality of third sets of pulses as afourth set of pulses, a fourth time interval separating successive thirdsets of pulses, the fourth time interval being at least ten times theduration of the third level time interval.

In some embodiments, a distal portion of the ablation device may furtherinclude a radiopaque portion. In some embodiments, the second catheterdefines a lumen therethrough.

In some embodiments, a method of ablation via irreversibleelectroporation includes the steps of advancing an ablation devicetowards a pulmonary vein ostium. The ablation device may include a firstcatheter, a second catheter or tubular lumen, and anexpandable/inflatable member coupled to a distal end of the cathetershaft. The inflatable member may be flanked by electrodes mounted on thedevice proximal and distal to the inflatable member. A pulse waveformmay be generated. The pulse waveform may be delivered to the pulmonaryvein ostium via the electrodes on the ablation device.

In some embodiments, the expandable/inflatable member of the ablationdevice may be transitioned from a first configuration to a secondconfiguration. In some embodiments, transitioning theexpandable/inflatable member from the first configuration to the secondconfiguration includes infusing the expandable/inflatable member withdistilled or deionized water which may induce mechanically expansion. Insome embodiments, pulsed electric field ablation energy may be deliveredthrough the first set of electrodes and the second set of electrodes ofthe ablation device. In some embodiments, the ablation device isconfigured to generate an electric field intensity of between about 200V/cm and about 800 V/cm.

In some embodiments, the ablation device may include a handle. In someembodiments, a portion of the first catheter shaft proximal to theproximal or first set of electrodes can be deflectable, with thedeflection controlled by a knob or other control mechanism on thehandle. The method may further include the steps of deflecting a portionof the ablation device using the handle. For example, a second electrodemay be moved relative to the first electrode and the shape of theexpandable/inflatable member in the second configuration may be modifiedby infusion of distilled or deionized water through an infusion portattached to the handle, and the distal shaft may be deflected using adeflection knob on the handle.

In some embodiments, the method may include the steps of creating atransseptal opening into a left atrium, advancing a guidewire and asteerable sheath into the left atrium through the transseptal opening,and advancing the ablation device into a pulmonary vein over theguidewire. In some embodiments, the method may include the steps ofcreating a first access site in a patient, advancing the guidewirethrough the first access site and into a right atrium, advancing thedilator and a steerable sheath over the guidewire and into the rightatrium, advancing the dilator from the right atrium into the left atriumthrough an interatrial septum to create the transseptal opening, anddilating the transseptal opening using the dilator. In some embodiments,a second access site may be created in the patient for advancing acardiac pacing catheter. In some embodiments, the method may include thesteps of advancing the pacing catheter into a right ventricle,generating a pacing signal for cardiac stimulation of the heart usingthe cardiac stimulator, and applying the pacing signal to the heartusing the cardiac stimulator, and then delivering a pulsed electricfield voltage pulse waveform in synchronization with the pacing signalonce the ablation device with the inflatable member is suitablypositioned at a pulmonary vein ostium.

In some embodiments, the method may include the step of fluoroscopicallyimaging a radiopaque portion of the ablation device during one or moresteps. In some embodiments, the first access site is a femoral vein. Insome embodiments, the interatrial septum includes a fossa ovalis.

In some embodiments, the pulse waveform may include a first level of ahierarchy of the pulse waveform in the form of a first set of pulses,each pulse having a pulse time duration, a first time intervalseparating successive pulses. A second level of the hierarchy of thepulse waveform includes a plurality of first sets of pulses as a secondset of pulses, a second time interval separating successive first setsof pulses, the second time interval being at least three times theduration of the first time interval. A third level of the hierarchy ofthe pulse waveform includes a plurality of second sets of pulses as athird set of pulses, a third time interval separating successive secondsets of pulses, the third time interval being at least thirty times theduration of the second level time interval. In some of theseembodiments, the pulse waveform includes a fourth level of the hierarchyof the pulse waveform includes a plurality of third sets of pulses as afourth set of pulses, a fourth time interval separating successive thirdsets of pulses, the fourth time interval being at least ten times theduration of the third level time interval.

The systems, devices, and methods described herein may be used togenerate large electric field magnitudes at desired regions of interestto generate irreversible electroporation. An irreversibleelectroporation system as described herein may include a signalgenerator and a processor configured to apply one or more voltage pulsewaveforms to a set of electrodes to deliver energy to a region ofinterest. The pulse waveforms disclosed herein may aid in therapeutictreatment of cardiac arrhythmias such as atrial fibrillation. In orderto deliver the pulse waveforms generated by the signal generator, one ormore electrodes of the ablation device may have an insulated electricallead configured for sustaining a voltage potential of at least about 700V without dielectric breakdown of its corresponding insulation. In someembodiments, at least some of the electrodes may be independentlyaddressable such that each electrode may be controlled (e.g., deliverenergy) independently of any other electrode of the device.

The term “electroporation” as used herein refers to the application ofan electric field to a cell membrane to change the permeability of thecell membrane to the extracellular environment. The term “reversibleelectroporation” as used herein refers to the application of an electricfield to a cell membrane to temporarily change the permeability of thecell membrane to the extracellular environment. For example, a cellundergoing reversible electroporation can observe the temporary and/orintermittent formation of one or more pores in its cell membrane thatclose up upon removal of the electric field. The term “irreversibleelectroporation” as used herein refers to the application of an electricfield to a cell membrane to permanently change the permeability of thecell membrane to the extracellular environment. For example, a cellundergoing irreversible electroporation can observe the formation of oneor more pores in its cell membrane that persist upon removal of theelectric field.

Pulse waveforms for electroporation energy delivery as disclosed hereinmay enhance the safety, efficiency and effectiveness of energy deliveryto tissue by reducing the electric field threshold associated withirreversible electroporation, thus yielding more effective ablativelesions with a reduction in total energy delivered. In some embodiments,the voltage pulse waveforms disclosed herein may be hierarchical andhave a nested structure. For example, the pulse waveform may includehierarchical groupings of pulses having associated timescales. In someembodiments, the methods, systems, and devices disclosed herein maycomprise one or more of the methods, systems, and devices described inone or more of International Application Serial No. PCT/US2016/057664,filed on Oct. 19, 2016, and titled “SYSTEMS, APPARATUSES AND METHODS FORDELIVERY OF ABLATIVE ENERGY TO TISSUE,” and U.S. patent application Ser.No. 16/405,515, filed on May 7, 2019, and titled “SYSTEMS, APPARATUSESAND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE,” the contents ofeach of which are hereby incorporated by reference in its entirety.

In some embodiments, the systems may further include a cardiacstimulator used to synchronize the generation of the pulse waveform to apaced heartbeat. The cardiac stimulator may electrically pace the heartwith a cardiac stimulator and ensure pacing capture to establishperiodicity and predictability of the cardiac cycle. A time windowwithin a refractory period of the periodic cardiac cycle may be selectedfor voltage pulse waveform delivery. Thus, voltage pulse waveforms maybe delivered in the refractory period of the cardiac cycle so as toavoid disruption of the sinus rhythm of the heart. In some embodiments,an ablation device may include one or more catheters, guidewires,expandable/inflatable members, and electrodes. The ablation device maytransform into different configurations (e.g., deflated and inflated) toposition the device within an endocardial space.

Generally, to ablate tissue, one or more catheters may be advanced in aminimally invasive fashion through vasculature to a target location. Themethods described here may include introducing a device into anendocardial space of the heart and disposing the device at the ostium ofa pulmonary vein. A pulse waveform may be generated and delivered toelectrodes of the device to ablate tissue. In some embodiments, thepulse waveform may be generated in synchronization with a pacing signalof the heart to avoid disruption of the sinus rhythm of the heart. Insome embodiments, the electrodes may be configured in anode-cathodesubsets. The pulse waveform may include hierarchical waveforms to aid intissue ablation and reduce damage to healthy tissue.

I. Systems

Overview

Disclosed herein are systems and devices configured for tissue ablationvia the selective and rapid application of voltage pulse waveforms toaid tissue ablation, resulting in irreversible electroporation.Generally, a system for ablating tissue described here may include asignal generator and an ablation device having one or more electrodesand an expandable/inflatable member (e.g., balloon) for the selectiveand rapid application of DC voltage to drive electroporation. Asdescribed herein, the systems and devices may be deployed endocardiallyto treat cardiac arrhythmias. Voltage pulse waveforms may be applied toa subset of the electrodes, with suitable anode/cathode electrodeselections. A pacing signal for cardiac stimulation may be generated andused to generate the pulse waveform by the signal generator insynchronization with the pacing signal.

Generally, the systems and devices described herein include one or morecatheters configured to ablate tissue in a ventricle of a heart. FIG. 1illustrates an ablation system (100) configured to deliver voltage pulsewaveforms. The system (100) may include an apparatus (120) including asignal generator (122), processor (124), memory (126), and cardiacstimulator (128). The apparatus (120) may be coupled to an ablationdevice (110), and optionally to a pacing device (130).

The signal generator (122) may be configured to generate pulse waveformsfor irreversible electroporation of tissue, such as, for example, apulmonary vein. For example, the signal generator (122) may be a voltagepulse waveform generator and be configured to deliver a pulse waveformto the ablation device (110). The return electrode (140) in someembodiments may be coupled to a patient (e.g., disposed on a patient'sback) to allow current to pass from the ablation device (110) throughthe patient and then to the return electrode (140). In otherembodiments, an electrode of the ablation device may serve as a return,such that a separate return electrode (140) may be absent. The processor(124) may incorporate data received from memory (126) to determine theparameters of the pulse waveform to be generated by the signal generator(122), while some parameters such as voltage can be input by a user. Thememory (126) may further store instructions to cause the signalgenerator (122) to execute modules, processes and/or functionsassociated with the system (100), such as pulse waveform generationand/or cardiac pacing synchronization. For example, the memory (126) maybe configured to store pulse waveform and/or heart pacing data for pulsewaveform generation and/or cardiac pacing, respectively.

In some embodiments, the ablation device (110) may include a catheterhaving an expandable/inflatable member (e.g., balloon) configured todeliver the pulse waveforms described in more detail below. In each ofthe embodiments described herein, the expandable/inflatable member maybe inflated using, for example, saline or, in some cases, anelectrically non-conducting or very poorly conducting fluid (e.g., gas,liquid such as distilled water, deionized water, etc.). Fluid may beinput through a lumen of a catheter coupled to the expandable/inflatablemember. For example, the ablation device (110) may be introduced into anendocardial space and positioned at the ostium of a pulmonary vein andinflated so that the inflatable member is well apposed or engaged at thewalls of the pulmonary vein, and then the pulse waveforms may bedelivered to ablate tissue. The ablation device (110) may include one ormore electrodes (112), which may, in some embodiments, be independentlyaddressable electrodes. Each electrode may include an insulatedelectrical lead configured to sustain a voltage potential of at leastabout 700 V without dielectric breakdown of its correspondinginsulation. In some embodiments, the insulation on each of theelectrical leads may sustain an electrical potential difference ofbetween about 200 V to about 3,000 V across its thickness withoutdielectric breakdown. For example, the electrodes (112) may be groupedinto one or more anode-cathode subsets such as, for example, a subsetincluding one proximal electrode and one distal electrode. In someembodiments, the distal electrode may include at least a portion of anexpandable/inflatable member. As used herein, proximal is towards ahandle of an ablation device and distal is towards a tip end of theablation device.

When used, the pacing device (130) may be suitably coupled to thepatient (not shown) and configured to receive a heart pacing signalgenerated by the cardiac stimulator (128). An indication of the pacingsignal may be transmitted by the cardiac stimulator (128) to the signalgenerator (122). Based on detection of the pacing signal by thegenerator, a voltage pulse waveform may be generated by the signalgenerator (122) for ablation delivery. In some embodiments, the signalgenerator (122) may be configured to generate the pulse waveform insynchronization with the indication of the pacing signal (e.g., suchthat the ablation delivery occurs during a refractory window of acardiac chamber). In some embodiments, the refractory window may be acommon refractory window of two cardiac chambers such as an atrium and aventricle. For example, in some embodiments, the common refractorywindow may start substantially immediately following a ventricularpacing signal (or after a very small delay) and last for a duration ofapproximately 250 ms or less thereafter. In such embodiments, an entirepulse waveform may be delivered within this duration.

The processor (124) may be any suitable processing device configured torun and/or execute a set of instructions or code. The processor may be,for example, a general purpose processor, a Field Programmable GateArray (FPGA), an Application Specific Integrated Circuit (ASIC), aDigital Signal Processor (DSP), and/or the like. The processor may beconfigured to run and/or execute application processes and/or othermodules, processes and/or functions associated with the system and/or anetwork associated therewith (not shown). The underlying devicetechnologies may be provided in a variety of component types, e.g.,metal-oxide semiconductor field-effect transistor (MOSFET) technologieslike complementary metal-oxide semiconductor (CMOS), bipolartechnologies like emitter-coupled logic (ECL), polymer technologies(e.g., silicon-conjugated polymer and metal-conjugated polymer-metalstructures), mixed analog and digital, and/or the like.

The memory (126) may include a database (not shown) and may be, forexample, a random access memory (RAM), a memory buffer, a hard drive, anerasable programmable read-only memory (EPROM), an electrically erasableread-only memory (EEPROM), a read-only memory (ROM), Flash memory, etc.The memory (126) may store instructions to cause the processor (124) toexecute modules, processes and/or functions associated with the system(100), such as pulse waveform generation and/or cardiac pacing.

The system (100) may be in communication with other devices (not shown)via, for example, one or more networks, each of which may be any type ofnetwork. A wireless network may refer to any type of digital networkthat is not connected by cables of any kind. However, a wireless networkmay connect to a wireline network in order to interface with theInternet, other carrier voice and data networks, business networks, andpersonal networks. A wireline network is typically carried over coppertwisted pair, coaxial cable or fiber optic cables. There are manydifferent types of wireline networks including, wide area networks(WAN), metropolitan area networks (MAN), local area networks (LAN),campus area networks (CAN), global area networks (GAN), like theInternet, and virtual private networks (VPN). Hereinafter, networkrefers to any combination of combined wireless, wireline, public andprivate data networks that are typically interconnected through theInternet, to provide a unified networking and information accesssolution.

Ablation Device

The systems described here may include one or more multi-electrodeablation devices configured to ablate tissue in a pulmonary vein of aheart for treating indications such as arrhythmia. FIG. 2A is a sideview of an ablation device (200) (e.g., structurally and/or functionallysimilar to the ablation device (110)) including a first catheter (203)(e.g., catheter shaft or outer shaft) defining a lumen, a secondcatheter (210) (e.g., a tubular guidewire or inner shaft defining alumen), and an inflatable member (207). The second catheter (210) may bedisposed within a lumen of the first catheter (203) and a chamber of theinflatable member (207) where the second catheter (210) may be slidablerelative to the first catheter (203). The inflatable member (e.g.,balloon) (207) may be coupled to the second catheter (210) such that thesecond catheter may pass through an inner chamber of the inflatablemember (207). A first electrode (213) may be disposed on a surface of adistal portion (217) of the first catheter (203) and may be eitherseparated from or attached to a proximal portion of the inflatablemember (207). A second electrode (220) may be disposed on a distalportion (223) of the second catheter (210) and may be either separatedfrom or attached to a distal portion of the inflatable member (207). Thedistal portion (223) of the second catheter (217) may be linearlymoveable and about a portion distal to the first catheter (203). In someembodiments, the second electrode (223) may be moveable relative to thefirst electrode (213). A proximal portion of the inflatable member (207)may be coupled to the distal portion of the first catheter (203).

A proximal end of the inflatable member (207) may be attached proximalto a distal end of the first catheter (203). The first electrode (213)may be disposed on the first catheter (203) just proximal to theproximal end of the inflatable member (207). In FIGS. 2A-2B, the secondcatheter or tubular lumen (210) is shown as extending from the distalend (217) of the first catheter (203) and out of a distal end of theinflatable member (207). The second electrode (220) is disposed on asurface of the second catheter (210) proximal to the distal end (223) ofthe second catheter (210). The distal end of the inflatable member (207)may be attached to the second catheter (210) just proximal to the secondelectrode (220).

In some embodiments, a handle (not shown) may be coupled to a proximalportion of the ablation device (200) and may include a bending mechanism(not shown) (e.g., knob, switch, pull wires) configured to deflect aportion of the second catheter (210) just proximal to the first catheter(203). For example, operation of a pull wire of the handle may increaseor decrease a curvature in a distal portion of the first catheter. Afluid port can attach to the handle for infusion of fluid such asdistilled water or deionized water to inflate the inflatable member. Inembodiments, the handle can incorporate a deployment mechanismconfigured to advance and retract the second catheter or guidewire lumen(210) such that a distance between the first electrode (213) and thesecond electrode (220) may be varied. For example, after the inflatablemember is positioned suitably in a pulmonary vein, it can be inflatedand well-apposed in the vein. Subsequently, the first electrode (213)and the second electrode (220) may be brought closer together byretracting the second catheter (210) relative to the first catheter(203). In this manner, the device may be configured for PEF ablationdelivery.

The inflatable member (207) may be configured to transition between afirst configuration (e.g., deflated inflatable member in FIG. 2B) and asecond configuration (e.g., inflated inflatable member in FIG. 2A). Theinflatable member (207) in the first configuration may be in a compact,deflated state suitable for advancement through vasculature. Forexample, the inflatable member (207) in the first configuration may besubstantially empty of fluid, such as sterile distilled or deionizedwater or saline. In some embodiments, fluid may enter the inflatablemember (207) via an infusion port of a handle coupled to the ablationdevice. The inflatable member (207) in the second configuration may holda volume of saline or distilled or deionized water that fills andinflates the inflatable member (207) to an appropriate size and shape(e.g., having a diameter to contact a diameter of a pulmonary vein)under pressure from a syringe or other infusion device. The inflatablemember (207) may transition to an intermediate configuration between thefirst and second configuration as necessary, for example, to conform toa lumen or advance the device through vasculature. In some embodiments,the inflatable member may be pressurized using one or more of ahand-operated syringe, pump, infusion device, combinations thereof, andthe like. In some embodiments, an infusion pressure may be between about2 psi and about 20 psi.

Although FIGS. 2A and 2B depict an ablation device having one proximalelectrode (213) and one distal electrode (223), it should be appreciatedthat more electrodes can be used in other embodiments. For example, thefirst electrode (213) may include a set of electrodes (e.g., two or moreproximal electrodes formed along a length of the first catheter).Likewise, the second electrode (220) may include a set of electrodes(e.g., two or more distal electrodes formed along a length of the secondcatheter). In some embodiments, a diameter of the electrodes (213, 220)may be between about 1 mm and about 6 mm, including all values andsub-ranges in between. A length of the electrodes (213, 220) (measuredalong a longitudinal axis of the first and second catheters) may bebetween about 1 mm and about 8 mm, including all values and sub-rangesin between. In some embodiments, a set of electrodes disposed on asurface of the first catheter (e.g., a set of two or more proximalelectrodes (213)) may be spaced apart by between about 0.5 mm and about9 mm, including all values and sub-ranges in between. In someembodiments, a set of electrodes disposed on a surface of the secondcatheter (e.g., a set of two or more distal electrodes (220)) may bespaced apart by between about 0.5 mm and about 9 mm, including allvalues and sub-ranges in between. In some embodiments, the inflatablemember in a second configuration (e.g., inflated, deployed) may have anouter diameter (e.g., maximum width) of between about 20 mm and about 40mm, including all values and sub-ranges in between. In some embodiments,the inflatable member in a first configuration (e.g., deflated,undeployed state) may have a length (measured along a longitudinal axisof the second catheter) of between about 10 mm and about 80 mm,including all values and sub-ranges in between, when the first andsecond electrodes (213, 220) are maximally separated.

FIG. 3 illustrates an ablation device (300) including an inflatablemember (305) (e.g., structurally and/or functionally similar to theablation device (110, 200)) in a second configuration (e.g., inflated)and deployed coaxially at an ostium of a pulmonary vein (301). Theablation device (300) includes a first electrode (311) coupled to aproximal end of the inflatable member (305) and a second electrode (313)coupled to a distal end of the inflatable member (305). A first catheterand a second catheter (e.g., a guidewire catheter defining a lumen),similar to those described herein, are not shown in FIG. 3 for the sakeof clarity. In FIG. 3, the second catheter or guidewire lumen (notshown) has been retracted relative to the first catheter such that thefirst electrode (311) and second electrode (313) are minimallyseparated. When the inflatable member is in the second configuration andthe first and second electrodes (311, 313) are retracted towards eachother, a central region (308) of the inflatable member (305) maylikewise be retracted towards each other or pulled in such that theproximal and distal ends of the inflatable member (305) are broughtcloser together. In this manner, the first and second electrodes (311,313) may be at least partially surrounded by portions of the inflatablemember (305) (where the balloon is folded inward).

FIG. 4A is a cross-sectional side view of an ablation device (400)(e.g., structurally and/or functionally similar to the ablation device(110, 200, 300)) disposed at a pulmonary vein ostium (402). Inparticular, a longitudinal axis of the ablation device (400) is disposedat an angle relative to a longitudinal axis of the pulmonary vein. FIG.4B is a cross-sectional perspective view of an ablation zone (408) ofthe ablation device depicted in FIG. 4A disposed in a pulmonary vein(411). The ablation device (400) may include an inflatable member (404)and a first electrode (e.g., electrode proximal to the inflatable member(404)) and a second electrode (e.g., electrode distal to the inflatablemember (404)). The first and second electrodes may be configured as ananode-cathode pair to deliver ablation energy to tissue. The ablationzone (408) may form a continuous ring-like shape on the pulmonary veinostium (402) when the anode-cathode pair delivers energy that exceeds athreshold value required to generate irreversible electroporation.

FIG. 5A is a cross-sectional side view of an ablation device (500)(e.g., structurally and/or functionally similar to the ablation device(110, 200, 300, 400)) disposed in a pulmonary vein ostium (502) (e.g.,deployed coaxially). The ablation device (500) includes a firstelectrode (508) coupled to a proximal end of the inflatable member (505)and a second electrode (509) coupled to a distal end of the inflatablemember (505). Alternatively or in addition, the first and secondelectrodes may be respectively coupled to the distal portion of thefirst catheter proximal to the inflatable member and to the distalportion of the second catheter/guidewire lumen distal to the inflatablemember. A first catheter or outer shaft and a second catheter or innershaft (e.g., a guidewire lumen), similar to those described herein, arenot shown in FIGS. 5A-5B for the sake of clarity. In FIG. 5A, theinflatable member (505) when inflated may form a frustum shape (e.g., atrapezoidal shape when viewed in lateral section). In some embodiments,a diameter of the inflatable member (505) at its widest portion may bebetween about 20 mm and about 40 mm, including all values and sub-rangesin between. A length of the inflatable member (505) (measured along alongitudinal axis of the first and second catheter) when fully deployedmay be between about 3 mm and about 30 mm, including all values andsub-ranges in between. FIG. 5B is a cross-sectional side view of theablation device (500) depicted in FIG. 5A where a longitudinal axis ofthe ablation device (500) is disposed at an angle relative to alongitudinal axis of the pulmonary vein (502).

FIG. 6A is a cross-sectional side view of an ablation device (600)(e.g., structurally and/or functionally similar to the ablation device(110, 200, 300, 400, 500)) disposed in a pulmonary vein ostium (603)(e.g., deployed coaxially). The ablation device (600) includes a firstelectrode (609) coupled to a proximal end of the inflatable member (606)and a second electrode (611) coupled to a distal end of the inflatablemember (606). Additionally or alternatively, the first and secondelectrodes may be respectively coupled to the distal portion of thefirst catheter/outer shaft proximal to the inflatable member and to thedistal portion of the second catheter/guidewire lumen distal to theinflatable member. A first catheter/outer shaft and a second catheter(e.g., an inner shaft defining a lumen), similar to those describedherein, are not shown in FIGS. 6A-6B for the sake of clarity. Theinflatable member (606) in the inflated configuration may form arhombus-like shape in a lateral view, as shown in FIG. 6A. FIG. 6B is alateral section view of an ablation zone (610) of the ablation device(600) depicted in FIG. 6A disposed in a pulmonary vein (603). The firstand second electrodes (609, 611) may be configured as an anode-cathodepair to deliver ablation energy to tissue. The ablation zone (610) mayform a ring-like shape on the pulmonary vein ostium (603) when theanode-cathode pair delivers energy that exceeds a threshold valuerequired to generate irreversible electroporation.

FIG. 7 is a schematic cross-sectional side view of an ablation device(700) (e.g., structurally and/or functionally similar to the ablationdevice (110, 200, 300, 400, 500, 600)). The ablation device (700) mayinclude a first catheter (703) (e.g., outer catheter shaft) defining alumen, a second catheter (705) (e.g., an inner shaft defining a lumen),and an inflatable member (710). The second catheter (705) may bedisposed within a lumen of the first catheter (703) and a chamber of theinflatable member (710) where the second catheter (705) may be slideablerelative to the first catheter (703). The inflatable member (e.g.,balloon) (710) may be coupled to the second catheter (705) such that thesecond catheter (705) may pass through an inner chamber of theinflatable member (710). A first electrode (707) may be disposed on asurface of a distal portion of the first catheter (703) and justproximal to the inflatable member (710). A second electrode (709) may bedisposed on a distal portion (712) of the second catheter (705) and justdistal to the inflatable member (710). The second catheter (705) may belinearly slideable relative to the first catheter (703). Thus, thesecond electrode (709) may be linearly slideable relative to the firstelectrode (707). A proximal portion of the inflatable member (710) maybe coupled to the distal portion of the first catheter (703). In FIG. 7,the inflatable member (710) may form an approximately rhombus-likeshape.

In some embodiments, the ablation device (700) may include a handle (notshown) coupled to a proximal portion of the ablation device (700) andmay include a mechanism (not shown) (e.g., knob, switch, pull wires)configured to advance and retract the second catheter or guidewire (705)relative to the first catheter (703) such that a distance between thefirst electrode (707) and the second electrode (709) may be varied. Forexample, the first electrode (707) and the second electrode (709) may bebrought closer together by retracting the second catheter (705) relativeto the first catheter (703). In FIG. 7, a central portion (713) of adistal end of the inflatable member (710) is shown as retracted toward aproximal end of the inflatable member (710).

When suitably inflated, a proximal major portion (715) and a distalmajor portion (719) of the inflatable member (710) may be angledrelative to a longitudinal axis of the first catheter (703) such that asurface of the inflatable member (710) forms an angle (731) with respectto the longitudinal axis that is greater than about 45 degrees. In someembodiments, a middle portion (721) of the inflatable member (710) maybe relatively short compared to the major portions (715, 719).

Although FIG. 7 depicts an ablation device having one proximal electrode(707) and one distal electrode (709), it should be appreciated that moreelectrodes can be used in other embodiments. For example, the firstelectrode (707) may include a set of electrodes (e.g., two or moreproximal electrodes). Likewise, the second electrode (709) may include aset of electrodes (e.g., two or more distal electrodes). In someembodiments, a diameter of the electrodes (707, 709) may be betweenabout 1 mm and about 6 mm, including all values and sub-ranges inbetween. A length of the electrodes (707, 709) (measured along alongitudinal axis of the first and second catheters) may be betweenabout 1 mm and about 8 mm, including all values and sub-ranges inbetween. In some embodiments, a set of electrodes disposed on a surfaceof the first catheter (703) (e.g., a set of two or more proximalelectrodes (707)) may be spaced apart by between about 0.5 mm and about9 mm, including all values and sub-ranges in between. In someembodiments, a set of electrodes disposed on a surface of the secondcatheter (705) (e.g., a set of two or more distal electrodes (709)) maybe spaced apart by between about 0.5 mm and about 9 mm, including allvalues and sub-ranges in between. In some embodiments, the inflatablemember (710) in a second configuration (e.g., inflated) may have anouter diameter of between about 20 mm and about 40 mm, including allvalues and sub-ranges in between. In some embodiments, the inflatablemember (710) in a first configuration (e.g., deflated, undeployed state)may have a length (measured along a longitudinal axis of the secondcatheter) of between about 10 mm and about 80 mm, including all valuesand sub-ranges in between, when the first and second electrodes (707,709) are maximally separated. In a fully deployed state with the secondcatheter (705) retracted for minimal separation between the first andsecond electrodes (707, 709), a length of the inflatable member (710)(measured along a longitudinal axis of the first catheter (703) may bebetween about 3 mm and about 30 mm, including all values and sub-rangesin between.

FIG. 8 is a schematic cross-sectional side view of an ablation device(800) (e.g., structurally and/or functionally similar to the ablationdevice (110, 200, 300, 400, 500, 600, 700)). The ablation device (800)may include a first catheter (803) (e.g., outer catheter shaft) defininga lumen, a second catheter (805) (e.g., an inner shaft defining aguidewire lumen), and an inflatable member (810). The second catheter(805) may be disposed within a lumen of the first catheter (803) and achamber of the inflatable member (810) where the second catheter (805)may be slidable relative to the first catheter (803). The inflatablemember (e.g., balloon) (810) may be coupled to the second catheter (805)such that the second catheter (805) may pass through an inner chamber ofthe inflatable member (810). A first electrode (807) may be disposed ona surface of a distal portion of the first catheter (803) and justproximal to the inflatable member (810). A second electrode (809) may bedisposed on a distal portion (812) of the second catheter (805) and justdistal to the inflatable member (810). The second catheter (805) may belinearly slideable relative to the first catheter (803). Thus, thesecond electrode (809) may be slideable relative to the first electrode(807). A proximal portion of the inflatable member (810) may be coupledto the first catheter (803) and a distal portion of the inflatablemember (810) may be coupled to the second catheter (805) such that thesecond catheter (805) may pass through an inner chamber of theinflatable member (810).

In some embodiments, the ablation device (800) may include a handle (notshown) coupled to a proximal portion of the ablation device (800) andmay include a mechanism (not shown) (e.g., knob, switch, pull wires)configured to advance and retract the second catheter (805) such that adistance between the first electrode (807) and the second electrode(809) may be varied. For example, the first electrode (807) and thesecond electrode (809) may be brought closer together by retracting thesecond catheter or guidewire (805) relative to the first catheter (803).In FIG. 8, a central portion (813) of a distal end of the inflatablemember (810) is shown as retracted toward a proximal end of theinflatable member (810) using a handle and a bending mechanism asdescribed herein.

When suitably inflated, a proximal major portion (815) and a distalmajor portion (819) of the inflatable member (810) may be gently curvedwith the surface locally having an angle relative to a longitudinal axisof the first catheter (803) such that a surface of the inflatable member(810) locally forms an angle (831) with respect to the longitudinalaxis. In some embodiments, a middle portion (821) of the inflatablemember (810) may be relatively short in length compared to the majorportions (815, 819). In some embodiments, the major portions (815, 819)may be gently curved with steep slopes with respect to the longitudinalaxis (825) of the first catheter (803). In FIG. 8, a local tangent (829)to a surface of the inflatable member (i.e., the component of the localtangent in the plane defined by radial and axial directions) may form anangle (831) with the longitudinal axis (825) that is greater than about45 degrees.

In some embodiments, a middle portion (821) of the inflatable member(810) may be relatively short in length compared to the major portions(815, 819). When the inflatable member (810) is inflated (e.g., suitablypressurized), the middle portion (821) may bulge as shown in FIG. 8. Insome embodiments, the middle portion (821) of the inflatable member(810) may be constructed of thinner material compared to the majorportions (815, 819). For example, the thickness of a wall of aninflatable member (810) of the major portions (815, 819) may be at least20% larger than the thickness of the wall at the middle portion (821).In some embodiments, the thickness of a wall of an inflatable member(810) of the major portions (815, 819) may be at least 50% larger thanthe thickness of the wall at the middle portion (821). In someembodiments, the thickness of a wall of an inflatable member (810) ofthe major portions (815, 819) may be at least 100% larger than thethickness of the wall at the middle portion (821).

FIG. 10 is a schematic side view of portion of the wall (1000) of anuninflated inflatable member including a proximal portion (1003), amiddle portion (1005), and a distal portion (1007). FIG. 10 illustratesschematically that the thickness (1011) of the proximal portion andthickness (1013) of the distal portion may be significantly larger thanthe thickness (1012) of the middle portion.

FIG. 11 is a schematic side view of a portion of a wall (1700) of aninflatable member of an ablation device, including a proximal portion(1703), a middle portion (1705), and a distal portion (1707), asarranged along a longitudinal or central axis (1710) of the inflatablemember. Any of the inflatable members described herein (e.g., inflatablemembers 207, 305, 404, 505, 606, etc.) can have a wall that isstructurally and/or functionally similar to the wall (1700) depicted inFIG. 11. The proximal portion (1703) of the wall (1700) can have alength L1 extending along the longitudinal axis (1710), the middleportion (1705) of the wall (1700) can have a length L2 extending alongthe longitudinal axis (1710), and the distal portion (1707) of the wall(1700) can have a length L3 extending along the longitudinal axis(1710). The lengths L1 and L3 can be greater than L2, with the ratiosL1/L2 and L3/L2 being greater than three.

As depicted in FIG. 11, the proximal portion (1703) of the wall (1700)of the inflatable member can have a maximum thickness D1, the middleportion (1705) of the wall (1700) can have a minimum thickness D2, andthe distal portion (1707) of the wall (1700) can have a maximumthickness D3. In some embodiments, thicknesses D1 and D3 of the proximaland distal portions (1703, 1707), respectively, can be equal to oneanother (or about equal to one another), and the thickness D2 of themiddle portion (1705) can be equal to or less than about a third of thethicknesses D1 and D3.

Although FIG. 8 depicts an ablation device having one proximal electrode(807) and one distal electrode (809), it should be appreciated that moreelectrodes can be used in other embodiments. For example, the firstelectrode (807) may include a set of electrodes (e.g., two or moreproximal electrodes). Likewise, the second electrode (809) may include aset of electrodes (e.g., two or more distal electrodes). In someembodiments, a diameter of the electrodes (807, 809) may be betweenabout 1 mm and about 6 mm, including all values and sub-ranges inbetween. A length of the electrodes (807, 809) (measured along alongitudinal axis of the first and second catheters) may be betweenabout 1 mm and about 8 mm, including all values and sub-ranges inbetween. In some embodiments, a set of electrodes disposed on a surfaceof the first catheter (803) (e.g., a set of two or more proximalelectrodes (807)) may be spaced apart by between about 0.5 mm and about9 mm, including all values and sub-ranges in between. In someembodiments, a set of electrodes disposed on a surface of the secondcatheter (805) (e.g., a set of two or more distal electrodes (809)) maybe spaced apart by between about 0.5 mm and about 9 mm, including allvalues and sub-ranges in between. In some embodiments, the inflatablemember (810) in a second configuration (e.g., inflated) may have anouter diameter of between about 20 mm and about 40 mm, including allvalues and sub-ranges in between. In some embodiments, the inflatablemember (810) in a first configuration (e.g., deflated, undeployed state)may have a length (measured along a longitudinal axis of the secondcatheter) of between about 10 mm and about 80 mm, including all valuesand sub-ranges in between, when the first and second electrodes (807,809) are maximally separated. In a fully deployed state with the secondcatheter (805) retracted for minimal separation between the first andsecond electrodes (807, 809), a length of the inflatable member (810)(measured along a longitudinal axis of the first catheter (803) may bebetween about 3 mm and about 30 mm, including all values and sub-rangesin between.

FIG. 9 is a perspective view of an ablation device (900) (e.g.,structurally and/or functionally similar to the ablation device (110,(801))). In particular, the ablation device (900) corresponds to aperspective view of the ablation device (800) depicted in FIG. 8. Theablation device (900) may include a first catheter (903) (e.g., an outercatheter shaft) defining a lumen, a second catheter (e.g., inner shaftor guidewire lumen) (whose tip (912) is shown), and an inflatable member(910). The second catheter may be disposed within a lumen of the firstcatheter (903) and a chamber of the inflatable member (910) where thesecond catheter may be slideable relative to the first catheter (903).The inflatable member (e.g., balloon) (910) may be coupled to the secondcatheter such that the second catheter may pass through an inner chamberof the inflatable member (910). A first electrode (907) may be disposedon a surface of a distal portion of the first catheter (903) andseparated from the inflatable member (910). A second electrode (909) maybe disposed on a distal portion (912) of the second catheter andseparated from the inflatable member (910). The second catheter may belinearly slideable relative to the first catheter (903). Thus, thesecond electrode (909) may be slideable relative to the first electrode(907). A proximal portion of the inflatable member (910) may be coupledto the distal portion of the first catheter (903). A proximal majorportion (915) and a distal major portion (919) of the inflatable member(910) may be gently curved with the surface locally having an anglerelative to a longitudinal axis of the first catheter (903). In someembodiments, a middle portion (921) of the inflatable member (910) maybe relatively short in length compared to the major portions (915, 919).In some embodiments, the major portions (915, 919) may be gently curvedwith steep slopes with respect to a longitudinal axis of the firstcatheter (903).

FIGS. 12A and 12B depict different views of an ablation device (1800),which can include components that are structurally and/or functionallysimilar to those of other ablation devices described herein. Theablation device (1800) can include a first electrode (1809) coupled to aproximal end of an inflatable member (1806), and a second electrode(1811) coupled to a distal end of the inflatable member (1806). In someembodiments, the second electrode (1811) can be coupled to an innercatheter or inner shaft or guidewire lumen, which in turn can beattached to a proximal handle (not depicted) for deploying the ablationdevice (1800). For example, the ablation device (1800) can be deployedby moving (e.g., pulling) the inner shaft proximally such that thesecond electrode (1811) is pulled toward the first electrode (1809) andthe inflatable member (1806) is inflated. Once deployed, the ablationdevice (1800) can be locked in place with an appropriate lockingmechanism, e.g., a locking mechanism disposed in the handle.

The inflatable member (1806) in the inflated and deployed configurationcan form a conical shape, such as shown in FIGS. 12A and 12B. In thedeployed configuration, which is shown in more detail in FIG. 13, theinflatable member (1806) can have a maximum width W, a height H, androunded sides (e.g., a side portion) with a radius of curvature R. Insome embodiments, e.g., when the inflatable member (1806) is designedfor use within a pulmonary vein of a heart, the width W can be less thanabout 40 mm, the height H can be less than about 25 mm, and the radius Rcan be less than about 15 mm.

In some embodiments, the first and second electrodes (1809, 1811) can bestructurally similar. For example, each of the first and secondelectrodes (1809, 1811) can have an outer diameter of about 1 mm toabout 7 mm and a length of about 1 mm to about 15 mm. In someembodiments, the second electrode (1811) can have a rounded oratraumatic shape, e.g., as depicted in FIG. 14. The inner shaft orguidewire lumen can be used to pass a guidewire through it to assistwith engaging a pulmonary vein, so that the catheter can be delivered tothe target anatomy over the guidewire.

In some embodiments, a proximal portion of the inflatable member (1806)in the deployed configuration can be angled relative to a longitudinalaxis of the ablation device (1800) by an angle A1, and a distal portionof the inflatable member (1806) can be angled relative to thelongitudinal axis of the ablation device (1800) by an angle A2. In someembodiments, angle A2 can be greater than angle A1, such that theinflatable member (1806) when deployed has an asymmetrical shape. Forexample, in some embodiments, angle A1 can lie in the range betweenabout 50 degrees and about 75 degrees, while angle A2 can be betweenabout 80 degrees and about 90 degrees.

FIG. 14 depicts a cross-sectional side view of an ablation device(1900), e.g., including components that are structurally and/orfunctionally similar to those of other ablation devices describedherein, while being disposed in a pulmonary vein ostium (1901) of aheart. In particular, similar to ablation device (1800), ablation device(1900) includes two electrodes (1909, 1911) disposed on opposite sidesof an inflatable member (1906). Electrode (1911) disposed at a distalend of the inflatable member (1906) can have a rounded or atraumatic tip(1911 a). When deployed, the inflatable member (1906) of the ablationdevice (1900) can have sides that engage with a wall (1902) of thepulmonary vein ostium (1901) and can hold the ablation device (1900)relative to the pulmonary vein ostium (1901). In the arrangementdepicted in FIG. 14, the ablation device (1900) can be held such thatits longitudinal axis is generally aligned with a longitudinal axis ofthe pulmonary vein ostium (1901), with a proximal side of the inflatablemember (1906) facing the blood pool (1903) of the heart chamber.Alternatively, the ablation device (1900) can be held at otherorientations with respect to the pulmonary vein ostium (1901) andgenerate different ablation zones within the surrounding tissue.

When oriented as shown in FIG. 14, the electrodes (1909, 1911) cangenerate an ablation zone (1920) when they are configured as ananode-cathode pair for delivering ablative energy, e.g., viairreversible electroporation as further described herein. The inflatablemember (1906) can be formed of an insulating material and, as orientatedand shaped, can direct the electric field generated by the electrodes(1909, 1911) toward the wall (1902) of the pulmonary vein ostium (1901).

Each of the ablation devices (110, 200, 300, 400, 500, 600, 700, 800,900, 1800, 1900, etc.) described herein may include a handle (not shown)that may, in some embodiments, be coupled to a proximal portion of theablation device and may include a mechanism (not shown) (e.g., knob,switch, pull wires) configured to modify the location of the secondelectrode relative to the first electrode. For example, the firstelectrode and the second electrode may be brought closer together byretracting the second catheter or guidewire lumen relative to the firstcatheter. In some embodiments, the first catheter may have a deflectableportion proximal to the proximal electrode whose shape is controlled bya steering knob or other control on the catheter handle. In embodiments,the device is tracked over a guidewire positioned in a pulmonary veinthrough a steerable sheath, and deflection of the sheath can providesteering control for positioning the guidewire and inflatable member ofthe ablation catheter in a pulmonary vein. The inflatable member may beinflated through a fluid port attached to the catheter handle whereindistilled or deionized water can be infused under pressure. In thismanner, apposition of the ablation device to tissue may be provided at adesired position and orientation (e.g., at a pulmonary vein ostium).

The ablation devices described herein may be useful for forming lesionson endocardial surfaces, such as an inner surface of a pulmonary vein,as described herein. A distal portion of the inflatable member mayinclude and/or be formed in an atraumatic shape that reduces trauma totissue (e.g., prevents and/or reduces the possibility of tissuepuncture). The inflatable member may be sized for advancement into anendocardial space. A set of electrical leads and/or a fluid (e.g.,saline) may be disposed within the lumen of the first catheter.

In some embodiments, the electrodes may be shaped to conform to theshape of the catheter upon which they are disposed. For example, theelectrodes may be press fit (e.g., crimped) to a first catheter or outershaft, or attached using an adhesive with electrical leads attached tothe electrodes. The first catheter may include flexible portions (e.g.,may be deflectable) to enhance flexibility and allow the device to bedeflected.

Each of the electrodes of any of the ablation devices discussed hereinmay be connected to an insulated electrical lead (not shown) leading toa handle (not shown) coupled to a proximal portion of the firstcatheter. The insulation on each of the electrical leads may sustain anelectrical potential difference of at least 700 V across its thicknesswithout dielectric breakdown. In other embodiments, the insulation oneach of the electrical leads may sustain an electrical potentialdifference of between about 200 V to about 3,000 V across its thicknesswithout dielectric breakdown, including all values and sub-ranges inbetween. This allows the electrodes and inflatable member coupledthereto to effectively deliver electrical energy and to ablate tissuethrough irreversible electroporation. The electrodes may, for example,receive pulse waveforms generated by a signal generator (122) asdiscussed above with respect to FIG. 1.

For each of the ablation devices discussed herein, the electrodes mayinclude biocompatible metals such as titanium, palladium, gold, silver,platinum or a platinum alloy. For example, the electrode may preferablyinclude platinum or a platinum alloy. In some embodiments, the proximalelectrodes may have a biocompatible coating that permits capacitivevoltage delivery with biphasic waveforms. Each electrode may include anelectrical lead having sufficient electrical insulation to sustain anelectrical potential difference of at least 700 V across its thicknesswithout dielectric breakdown. In other embodiments, the insulation oneach of the electrical leads may sustain an electrical potentialdifference of between about 200 V to about 3,000 V across its thicknesswithout dielectric breakdown, including all values and sub-ranges inbetween. The insulated electrical leads may run to the proximal handleportion of the ablation device from where they may be connected to asuitable electrical connector. The first catheter may be made of aflexible polymeric material such as Teflon, Nylon, Pebax, etc.

In some embodiments, the inflatable members as described herein may havean expandable structure and may be composed of any of a variety ofinsulating or dielectric materials including, but not limited topolyvinyl chloride (PVC), polyethylene (PE), cross-linked polyethylene,polyolefins, polyolefin copolymer (POC), polyethylene terephthalate(PET), polyester, nylon, polymer blends, polyester, polyimide,polyamides, polyurethane, silicone, polydimethylsiloxane (PDMS), PEBAX,and the like. Preferred embodiments can be composed of polyurethane orsilicone. Together with the use of distilled or deionized water toinflate the inflatable member, the inflatable member serves as aneffective insulator during delivery of the Pulsed Electric Fieldwaveform and drives the electric field to the region outside theinflatable member or balloon and surrounding the balloon.

II. Methods

Also described here are methods for ablating tissue in a pulmonary vein(e.g., pulmonary vein in the left atrium) using the systems and devicesdescribed above. Generally, the methods described here includeintroducing and disposing a device in an ostium of a pulmonary vein. Apulse waveform may be delivered by one or more electrodes and aninflatable member (e.g., balloon) of the device to ablate tissue. Insome embodiments, a cardiac pacing signal may synchronize the deliveredpulse waveforms with the cardiac cycle. Additionally or alternatively,the pulse waveforms may include a plurality of levels of a hierarchy toreduce total energy delivery. The tissue ablation thus performed may bedelivered in synchrony with paced heartbeats and with less energydelivery to reduce damage to healthy tissue. It should be appreciatedthat any of the ablation devices described herein may be used to ablatetissue using the methods discussed below as appropriate.

Generally, and as illustrated in FIGS. 20A-20B, a method (1600) includesthe introduction of a device (e.g., ablation device, such as theablation devices (110, 200, 300, 400, 500, 600, 700, 800, 900) into anendocardial space of a pulmonary vein. The ablation device may beintroduced in a first or deflated configuration and transitioned to asecond or inflated configuration in an ostium of a pulmonary vein. Oncepositioned, voltage pulse waveforms may be applied to tissue during arefractory period of the cardiac cycle. Electrophysiology data of thecardiac chamber may be recorded to determine efficacy of the ablation.

The method (1600) may begin with creating an access site in a patient(1602). For example, a first access site may be via a femoral vein ofthe patient. A guidewire may be advanced into the access site via thefemoral vein and into the right atrium of the patient (1604). A dilatorand a deflectable sheath may be advanced over the guidewire and into theright atrium (1606). The sheath may, for example, be configured fordeflecting up to about 180 degrees or more. The dilator may be advancedfrom the right atrium into the left atrium through the septum (1608) tocreate a transseptal opening. For example, the dilator may be advancedfrom the right atrium into the left atrium through the interatrialseptum to create the transseptal opening. The interatrial septum mayinclude the fossa ovalis of the patient. The transseptal opening may bedilated using the dilator (1610). For example, the dilator may beadvanced out of the sheath and used to puncture the fossa ovalis tocreate the transseptal opening (assuming the patient is heparinized).Alternatively, a transseptal needle (e.g., Brockenbrough needle) may beused to create the transseptal opening. The sheath may be advanced fromthe right atrium into the left atrium (1612) through the transseptalopening. An ablation device may be advanced into the left atrium overthe guidewire (1614), with the second catheter or guidewire lumen of theablation device tracking over the guidewire.

In some embodiments, the ablation device may include a catheter lumenand a set of insulated electrical leads extending through the lumen. Inembodiments, a thin microcatheter with a circular distal shape withelectrodes mounted on the circular shape may be introduced through thesecond catheter or guidewire lumen into the pulmonary vein, and used torecord intracardiac ECG data to confirm successful ablation.

Still referring to FIGS. 20A-20B, a second access site may be created inthe patient to advance a lead or catheter for cardiac stimulation intothe patient's heart. For example, the second access site may be via ajugular vein of the patient. The device for cardiac stimulation may beadvanced into the right ventricle through the second access site (1620)(e.g., near the apex of the right ventricle). A pacing signal may begenerated by a cardiac stimulator and applied to the heart for cardiacstimulation of the heart. An indication of the pacing signal may betransmitted from the cardiac stimulator to the signal generator. In someembodiments, the operator may confirm the pacing capture and determinethat the ventricle is responding to the pacing signal as intended. Forexample, pacing capture may be confirmed on an ECG display on a signalgenerator. Confirmation of pacing capture is a safety feature in thatablation is delivered in synchrony with pacing through enforcedperiodicity of a Q-wave through pacing. Likewise, in some embodiments,an additional pacing catheter may be used for example to pace the rightatrium in addition to the right ventricle, and ablation can be deliveredduring the common refractory window of both cardiac chambers.

The ablation device may be advanced towards a target pulmonary vein(1622) for delivering a pulse waveform configured for tissue ablation.In particular, the ablation device in the second configuration may beadvanced towards a pulmonary vein of the heart to engage tissue surface.The sheath may be deflected as needed to direct the ablation devicetowards the target vein. The inflatable member may be transitioned to asecond configuration where the inflatable member inflates to contact theinflatable member against the pulmonary vein. Once the ablation deviceis in position within the heart to deliver one or more pulse waveforms,an extension cable may be used to electrically couple a signal generatorto a proximal end of the handle of the ablation device. After pacing theright ventricle using the pacing device (1624), the pulse waveform maybe delivered to the target site using the ablation device to ablatetissue. The pulse waveform may be delivered in synchronization with thepacing signal.

While examples of ablation devices configured for delivery ofirreversible electroporation pulsed electric field therapy have beendescribed here, the examples described herein are provided for exemplarypurposes only and those skilled in the art may devise other variationswithout departing from the scope of the present invention. For example,a range and variety of materials, polyhedral sides, electrode diameters,device dimensions, voltage levels, proximal electrodes, and other suchdetails are possible and may be implemented as convenient for theapplication at hand without departing from the scope of the presentinvention. In embodiments where the distal shaft of the catheter isdeflectable, the catheter shaft may undergo a range of deflections bycontrolling deflection from a catheter handle.

As discussed herein, the pulse waveform may be generated by a signalgenerator coupled to the ablation device. The signal generator may beelectrically coupled to a proximal end of a handle of the ablationdevice. For example, an extension cable may electrically couple thesignal generator to the proximal end of the handle. In some embodiments,the pulse waveform may include a time offset with respect to the pacingsignal. In some embodiments, the pulse waveform may include a firstlevel of a hierarchy of the pulse waveform including a first set ofpulses. Each pulse has a pulse time duration and a first time intervalseparating successive pulses. A second level of the hierarchy of thepulse waveform may include a plurality of first sets of pulses as asecond set of pulses. A second time interval may separate successivefirst sets of pulses. The second time interval may be at least threetimes the duration of the first time interval. A third level of thehierarchy of the pulse waveform may include a plurality of second setsof pulses as a third set of pulses. A third time interval may separatesuccessive second sets of pulses. The third time interval may be atleast thirty times the duration of the second level time interval. Afourth level of the hierarchy of the pulse waveform may include aplurality of third sets of pulses as a fourth set of pulses. A fourthtime interval may separate successive third sets of pulses. The fourthtime interval may be at least ten times the duration of the third leveltime interval.

In other embodiments, the ablation device may be withdrawn from theheart over the guidewire and a mapping catheter may be advanced over theguidewire to record the post-ablation electrophysiology data of thetarget site. If the ablation is not successful (1630—NO) based on theelectrophysiology data and predetermined criteria, then the process mayreturn to step 1626 for delivery of additional pulse waveforms. Thepulse waveform parameters may be the same or changed for subsequentablation cycles.

If analysis of the electrophysiology data indicates that the ablation issuccessful (e.g., tissue portion is electrically silent) (1630—YES),then a determination may be made of other target portions to ablate(1632) (e.g., other pulmonary veins). Another target portion may beselected (1624) and the process may return to step 1622 when otherportions are to be ablated. When switching between target tissue, theinflatable member may be at least partially deflated, and the ablationdevice may be advanced towards another portion of tissue. If no otherportions are to be ablated (1632—NO), the ablation device, pacingcatheters, sheath, guidewire, and the like, may be removed from thepatient (1636).

It should be noted that for any of the steps described herein, aradiopaque portion of the ablation device may be fluoroscopically imagedto aid an operator. For example, visual confirmation may be performedthrough fluoroscopic imaging that the inflatable members in the secondconfiguration is in contact with and approximately centered in a vein,by means of a radio-opaque marker band placed on the distal portion ofthe device.

It should be understood that the examples and illustrations in thisdisclosure serve exemplary purposes and departures and variations suchas inflatable member characteristics, number of electrodes, and so oncan be built and deployed according to the teachings herein withoutdeparting from the scope of this invention.

Pulse Waveform

Disclosed herein are methods, systems and apparatuses for the selectiveand rapid application of pulsed electric fields/waveforms to effecttissue ablation with irreversible electroporation. The pulse waveform(s)as disclosed herein are usable with any of the systems (100), devices(e.g., 200, 300, 400, 500, 600, 700, 800, 900), and methods (e.g., 1600)described herein. Some embodiments are directed to pulsed high voltagewaveforms together with a sequenced delivery scheme for deliveringenergy to tissue via sets of electrodes. In some embodiments, peakelectric field values can be reduced and/or minimized while at the sametime sufficiently large electric field magnitudes can be maintained inregions where tissue ablation is desired. In some embodiments, a systemuseful for irreversible electroporation includes a signal generator anda processor capable of being configured to apply pulsed voltagewaveforms to a selected plurality or a subset of electrodes of anablation device. In some embodiments, the processor is configured tocontrol inputs whereby selected pairs of anode-cathode subsets ofelectrodes can be either simultaneously or sequentially triggered basedon a pre-determined sequence, and in one embodiment the sequenceddelivery can be triggered from a cardiac stimulator and/or pacingdevice. In some embodiments, the ablation pulse waveforms are applied ina refractory period of the cardiac cycle so as to avoid disruption ofthe sinus rhythm of the heart. One example method of enforcing this isto electrically pace the heart with a cardiac stimulator and ensurepacing capture to establish periodicity and predictability of thecardiac cycle, and then to define a time window well within therefractory period of this periodic cycle within which the ablationwaveform is delivered.

In some embodiments, the pulsed voltage waveforms disclosed herein arehierarchical in organization and have a nested structure. In someembodiments, the pulsed waveform includes hierarchical groupings ofpulses with a variety of associated timescales. Furthermore, theassociated timescales and pulse widths, and the numbers of pulses andhierarchical groupings, can be selected so as to satisfy one or more ofa set of Diophantine inequalities involving the frequency of cardiacpacing.

Pulsed waveforms for electroporation energy delivery as disclosed hereinmay enhance the safety, efficiency and effectiveness of the energydelivery by reducing the electric field threshold associated withirreversible electroporation, yielding more effective ablative lesionswith reduced total energy delivered.

FIG. 15 illustrates a pulsed voltage waveform in the form of a sequenceof rectangular double pulses, with each pulse, such as the pulse (1100)being associated with a pulse width or duration. The pulsewidth/duration can be about 0.5 microseconds, about 1 microsecond, about5 microseconds, about 10 microseconds, about 25 microseconds, about 50microseconds, about 100 microseconds, about 125 microseconds, about 140microseconds, about 150 microseconds, including all values andsub-ranges in between. The pulsed waveform of FIG. 15 illustrates a setof monophasic pulses where the polarities of all the pulses are the same(all positive in FIG. 15, as measured from a zero baseline). In someembodiments, such as for irreversible electroporation applications, theheight of each pulse (1100) or the voltage amplitude of the pulse (1100)can be in the range from about 400 volts, about 1,000 volts, about 5,000volts, about 10,000 volts, about 15,000 volts, including all values andsub ranges in between. As illustrated in FIG. 15, the pulse (1100) isseparated from a neighboring pulse by a time interval (1102), alsosometimes referred to as a first time interval. As examples, the firsttime interval can be about 1 microsecond, about 50 microseconds, about100 microseconds, about 200 microseconds, about 500 microseconds, about800 microseconds, about 1 millisecond including all values and subranges in between, in order to generate irreversible electroporation.

FIG. 16 introduces a pulse waveform with the structure of a hierarchy ofnested pulses. FIG. 16 shows a series of monophasic pulses such as pulse(1200) with pulse width/pulse time duration w, separated by a timeinterval (also sometimes referred to as a first time interval) such as(1202) of duration t1 between successive pulses, a number m1 of whichare arranged to form a group of pulses (1210) (also sometimes referredto as a first set of pulses). Furthermore, the waveform has a number m2of such groups of pulses (also sometimes referred to as a second set ofpulses) separated by a time interval (1212) (also sometimes referred toas a second time interval) of duration t2 between successive groups. Thecollection of m2 such pulse groups, marked by (1220) in FIG. 16,constitutes the next level of the hierarchy, which can be referred to asa packet and/or as a third set of pulses. The pulse width and the timeinterval t1 between pulses can both be in the range of microseconds tohundreds of microseconds, including all values and sub ranges inbetween. In some embodiments, the time interval t2 can be at least threetimes larger than the time interval t1. In some embodiments, the ratiot2/t1 can be in the range between about 3 and about 300, including allvalues and sub-ranges in between.

FIG. 17 further elaborates the structure of a nested pulse hierarchywaveform. In this figure, a series of m1 pulses (individual pulses notshown) form a group of pulses (1300) (e.g., a first set of pulses). Aseries of m2 such groups separated by an inter-group time interval(1310) of duration t2 (e.g., a second time interval) between one groupand the next form a packet (e.g., a second set of pulses). A series ofm3 such packets separated by time intervals (1312) of duration t3 (e.g.,a third time interval) between one packet and the next form the nextlevel in the hierarchy, a super-packet labeled (1320) (e.g., a third setof pulses) in the figure. In some embodiments, the time interval t3 canbe at least about thirty times larger than the time interval t2. In someembodiments, the time interval t3 can be at least fifty times largerthan the time interval t2. In some embodiments, the ratio t3/t2 can bein the range between about 30 and about 800, including all values andsub-ranges in between. The amplitude of the individual voltage pulses inthe pulse hierarchy can be anywhere in the range from 500 volts to 7,000volts or higher, including all values and sub ranges in between.

FIG. 18 provides an example of a biphasic waveform sequence with ahierarchical structure. In the example shown in the figure, biphasicpulses such as (1400) have a positive voltage portion as well as anegative voltage portion to complete one cycle of the pulse. There is atime delay (1402) (e.g., a first time interval) between adjacent cyclesof duration t1, and n1 such cycles form a group of pulses (1410) (e.g.,a first set of pulses). A series of n2 such groups separated by aninter-group time interval (1412) (e.g., a second time interval) ofduration t2 between one group and the next form a packet (1420) (e.g., asecond set of pulses). The figure also shows a second packet (1430),with a time delay (1432) (e.g., a third time interval) of duration t3between the packets. Just as for monophasic pulses, higher levels of thehierarchical structure can be formed as well. The amplitude of eachpulse or the voltage amplitude of the biphasic pulse can be anywhere inthe range from 500 volts to 7,000 volts or higher, including all valuesand sub ranges in between. The pulse width/pulse time duration can be inthe range from nanoseconds or even sub-nanoseconds to tens ofmicroseconds, while the delays t1 can be in the range from zero toseveral microseconds. The inter-group time interval t2 can be at leastten times larger than the pulse width. In some embodiments, the timeinterval t3 can be at least about twenty times larger than the timeinterval t2. In some embodiments, the time interval t3 can be at leastfifty times larger than the time interval t2.

Embodiments disclosed herein include waveforms structured ashierarchical waveforms that include waveform elements/pulses at variouslevels of the hierarchy. The individual pulses such as (1200) in FIG. 16comprise the first level of the hierarchy, and have an associated pulsetime duration and a first time interval between successive pulses. A setof pulses, or elements of the first level structure, form a second levelof the hierarchy such as the group of pulses/second set of pulses (1210)in FIG. 16. Among other parameters, associated with the waveform areparameters such as a total time duration of the second set of pulses(not shown), a total number of first level elements/first set of pulses,and second time intervals between successive first level elements thatdescribe the second level structure/second set of pulses. In someembodiments, the total time duration of the second set of pulses can bebetween about 20 microseconds and about 10 milliseconds, including allvalues and subranges in between. A set of groups, second set of pulses,or elements of the second level structure, form a third level of thehierarchy such as the packet of groups/third set of pulses (1220) inFIG. 16. Among other parameters, there is a total time duration of thethird set of pulses (not shown), a total number of second levelelements/second set of pulses, and third time intervals betweensuccessive second level elements that describe the third levelstructure/third set of pulses. The generally iterative or nestedstructure of the waveforms can continue to a higher plurality of levels,such as ten levels of structure, or more.

For example, a pulse waveform may include a fourth level of thehierarchy of the pulse waveform may include a plurality of third sets ofpulses as a fourth set of pulses, a fourth time interval separatingsuccessive third sets of pulses, the fourth time interval being at leastten times the duration of the third level time interval.

In some embodiments, hierarchical waveforms with a nested structure andhierarchy of time intervals as described herein are useful forirreversible electroporation ablation energy delivery, providing a gooddegree of control and selectivity for applications in different tissuetypes. A variety of hierarchical waveforms can be generated with asuitable pulse generator. It is understood that while the examplesherein identify separate monophasic and biphasic waveforms for clarity,it should be noted that combination waveforms, where some portions ofthe waveform hierarchy are monophasic while other portions are biphasic,can also be generated/implemented.

In some embodiments, the ablation pulse waveforms described herein areapplied during the refractory period of the cardiac cycle so as to avoiddisruption of the sinus rhythm of the heart. In some embodiments, amethod of treatment includes electrically pacing the heart with acardiac stimulator to ensure pacing capture to establish periodicity andpredictability of the cardiac cycle, and then defining a time windowwithin the refractory period of the cardiac cycle within which one ormore pulsed ablation waveforms can be delivered. FIG. 19 illustrates anexample where both atrial and ventricular pacing is applied (forinstance, with pacing leads or catheters situated in the right atriumand right ventricle respectively). With time represented on thehorizontal axis, FIG. 19 illustrates a series of ventricular pacingsignals such as (1500) and (1510), and a series of atrial pacing signals(1520, 1530), along with a series of ECG waveforms (1540, 1542) that aredriven by the pacing signals. As indicated in FIG. 19 by the thickarrows, there is an atrial refractory time window (1522) and aventricular refractory time window (1502) that respectively follow theatrial pacing signal (1522) and the ventricular pacing signal (1500). Asshown in FIG. 19, a common refractory time window (1550) of duration Trcan be defined that lies within both atrial and ventricular refractorytime windows (1522, 1502). In some embodiments, the electroporationablation waveform(s) can be applied in this common refractory timewindow (1550). The start of this refractory time window (1522) is offsetfrom the pacing signal (1500) by a time offset (1504) as indicated inFIG. 19. The time offset (1504) can be smaller than about 25milliseconds, in some embodiments. At the next heartbeat, a similarlydefined common refractory time window (1552) is the next time windowavailable for application of the ablation waveform(s). In this manner,the ablation waveform(s) may be applied over a series of heartbeats, ateach heartbeat remaining within the common refractory time window. Inone embodiment, each packet of pulses as defined above in the pulsewaveform hierarchy can be applied over a heartbeat, so that a series ofpackets is applied over a series of heartbeats, for a given electrodeset.

As used herein, the terms “about” and/or “approximately” when used inconjunction with numerical values and/or ranges generally refer to thosenumerical values and/or ranges near to a recited numerical value and/orrange. In some instances, the terms “about” and “approximately” may meanwithin ±10% of the recited value. For example, in some instances, “about100 [units]” may mean within ±10% of 100 (e.g., from 90 to 110). Theterms “about” and “approximately” may be used interchangeably.

Some embodiments described herein relate to a computer storage productwith a non-transitory computer-readable medium (also may be referred toas a non-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals per se (e.g., a propagating electromagnetic wavecarrying information on a transmission medium such as space or a cable).The media and computer code (also may be referred to as code oralgorithm) may be those designed and constructed for the specificpurpose or purposes. Examples of non-transitory computer-readable mediainclude, but are not limited to, magnetic storage media such as harddisks, floppy disks, and magnetic tape; optical storage media such asCompact Disc/Digital Video Discs (CD/DVDs), Compact Disc-Read OnlyMemories (CD-ROMs), and holographic devices; magneto-optical storagemedia such as optical disks; carrier wave signal processing modules; andhardware devices that are specially configured to store and executeprogram code, such as Application-Specific Integrated Circuits (ASICs),Programmable Logic Devices (PLDs), Read-Only Memory (ROM) andRandom-Access Memory (RAM) devices. Other embodiments described hereinrelate to a computer program product, which may include, for example,the instructions and/or computer code disclosed herein.

The systems, devices, and/or methods described herein may be performedby software (executed on hardware), hardware, or a combination thereof.Hardware modules may include, for example, a general-purpose processor(or microprocessor or microcontroller), a field programmable gate array(FPGA), and/or an application specific integrated circuit (ASIC).Software modules (executed on hardware) may be expressed in a variety ofsoftware languages (e.g., computer code), including C, C++, Java®, Ruby,Visual Basic®, and/or other object-oriented, procedural, or otherprogramming language and development tools. Examples of computer codeinclude, but are not limited to, micro-code or micro-instructions,machine instructions, such as produced by a compiler, code used toproduce a web service, and files containing higher-level instructionsthat are executed by a computer using an interpreter. Additionalexamples of computer code include, but are not limited to, controlsignals, encrypted code, and compressed code.

The specific examples and descriptions herein are exemplary in natureand embodiments may be developed by those skilled in the art based onthe material taught herein without departing from the scope of thepresent invention, which is limited only by the attached claims.

We claim:
 1. An apparatus, comprising: a first shaft having alongitudinal axis and defining a lumen; a second shaft disposed withinthe lumen and having a distal portion that extends from a distal portionof the first shaft, the second shaft moveable along the longitudinalaxis relative to the first shaft; a first electrode coupled to thedistal portion of the first shaft; a second electrode coupled to thedistal portion of the second shaft, the first and second electrodesconfigured to generate an electric field for ablating tissue; and aninflatable member disposed between the first and second electrodes, theinflatable member configured to transition from an undeployedconfiguration to a deployed configuration in response to the secondshaft being moved proximally relative to the first shaft, the inflatablemember in the deployed configuration configured to engage a wall of apulmonary vein ostium and direct the electric field generated by thefirst and second electrodes toward the wall.
 2. The apparatus of claim1, wherein the inflatable member in the deployed configuration includesat least a proximal portion or a distal portion that is angled greaterthan about 45 degrees relative to the longitudinal axis.
 3. Theapparatus of claim 1, wherein the inflatable member includes a wallhaving: a proximal portion; a distal portion; and a middle portiondisposed between the proximal and distal portions of the wall, themiddle portion having a minimum thickness that is less than a thicknessof the proximal and distal portions of the wall.
 4. The apparatus ofclaim 3, wherein a length of each of the proximal and distal portions ofthe inflatable member along the longitudinal axis is greater than alength of the middle portion along the longitudinal axis.
 5. Theapparatus of claim 4, wherein a ratio of the length of the proximalportion to the length of the middle portion and a ratio of the length ofthe distal portion to the length of the middle portion are greater thanabout three.
 6. The apparatus of claim 1, wherein the inflatable memberin the deployed configuration has a cross-sectional shape having a widthof less than about 40 mm, a height of less than about 25 mm, and a sideportion with a radius of curvature of less than about 15 mm.
 7. Theapparatus of claim 1, wherein the inflatable member in the deployedconfiguration has a cross-sectional shape having a maximum width ofbetween about 20 mm and about 40 mm.
 8. The apparatus of claim 1,wherein the first electrode is attached to a proximal portion of theinflatable member and the second electrode is attached to a distalportion of the inflatable member.
 9. The apparatus of claim 1, whereineach of the first and second electrodes has an outer diameter of about 1mm to 7 mm and a length along the longitudinal axis of about 1 mm toabout 15 mm.
 10. The apparatus of claim 1, wherein the second electrodehas a rounded distal end.
 11. An apparatus, comprising: a shaft having alongitudinal axis and defining a lumen; an inflatable member disposednear a distal portion of the shaft, the inflatable member configured totransition between an undeployed configuration and a deployedconfiguration, the inflatable member including a wall having a proximalportion, a distal portion, and a middle portion disposed between theproximal and distal portions of the wall, the middle portion having aminimum thickness that is less than a thickness of the proximal anddistal portions of the wall; and first and second electrodes disposed onopposite sides of the inflatable member along the longitudinal axis, thefirst and second electrodes configured to generate an electric field forablating tissue.
 12. The apparatus of claim 11, wherein the inflatablemember in the deployed configuration includes at least a proximalportion or a distal portion that is angled greater than about 45 degreesrelative to the longitudinal axis.
 13. The apparatus of claim 11,wherein the inflatable member in the deployed configuration isconfigured to engage a wall of a pulmonary vein ostium, the inflatablemember formed of an insulating material such that the inflatable memberin the deployed configuration directs the electric field generated bythe first and second electrodes toward the wall of the pulmonary veinostium.
 14. The apparatus of claim 11, wherein the minimum thickness ofthe middle portion is less than about a third of the thickness of atleast the proximal or distal portion of the wall.
 15. The apparatus ofclaim 11, wherein a length of each of the proximal and distal portionsof the inflatable member along the longitudinal axis is greater than alength of the middle portion along the longitudinal axis.
 16. Theapparatus of claim 15, wherein a ratio of the length of the proximalportion to the length of the middle portion and a ratio of the length ofthe distal portion to the length of the middle portion are greater thanabout three.
 17. The apparatus of claim 11, wherein the inflatablemember in the deployed configuration has a cross-sectional shape havinga width of less than about 40 mm, a height of less than about 25 mm, anda side portion with a radius of curvature of less than about 15 mm. 18.The apparatus of claim 11, wherein the inflatable member is fluidicallycoupled to an infusion device, the inflatable member configured totransition from the undeployed configuration to the deployedconfiguration in response to an infusion of fluid from the infusiondevice.
 19. The apparatus of claim 18, wherein the infusion of fluid isdelivered at an infusion pressure of between about 2 psi and about 20psi.
 20. A system, comprising: a signal generator configured to generatea pulse waveform; an ablation device coupled to the signal generator,the ablation device including: first and second electrodes configured toreceive the pulse waveform and generate an electric field for ablation;and an inflatable member formed of an insulating material and disposedbetween the first and second electrodes, the inflatable memberconfigured to transition between an undeployed configuration in whichthe inflatable member can be advanced to a pulmonary vein ostium to adeployed configuration in which the inflatable member can engage with awall of the pulmonary vein ostium, the inflatable member in the deployedconfiguration configured to direct the electric field toward the wall.21. The system of claim 20, wherein the ablation device furtherincludes: a first shaft having a longitudinal axis and defining a lumen;and a second shaft extending through the lumen, the second shaft movablerelative to the first shaft to bring proximal and distal ends of theinflatable member along the longitudinal axis closer to one another totransition the inflatable member from the undeployed state into thedeployed state.
 22. The system of claim 21, further comprising a handlecoupled to a proximal portion of the ablation device, the handleincluding a mechanism configured to move the second shaft relative tothe first shaft.
 23. The system of claim 22, wherein the handle furtherincludes a locking mechanism configured to lock a position of the secondshaft relative to the first shaft to maintain the inflatable member inthe deployed configuration.
 24. The system of claim 20, furthercomprising an infusion device configured to pressurize the inflatablemember to transition the inflatable member from the undeployedconfiguration to the deployed configuration.
 25. The system of claim 20,wherein the inflatable member in the deployed configuration has across-sectional shape having a width of less than about 40 mm, a heightof less than about 25 mm, and a side portion with a radius of curvatureof less than about 15 mm.
 26. A method, comprising: retracting an innershaft of an ablation device relative to an outer shaft of the ablationdevice, the inner shaft disposed within a lumen of the outer shaft;transitioning, in response to retracting the inner shaft relative to theouter shaft, an inflatable member of the ablation device from anundeployed configuration to a deployed configuration in which a sideportion of the inflatable member engages a wall of a pulmonary veinostium; and delivering, after the transitioning, a pulse waveform tofirst and second electrodes of the ablation device such that the firstand second electrodes generate an electric field for ablating the wallof the pulmonary vein ostium, the first and second electrodes disposedon opposite sides of the inflatable member.
 27. The method of claim 26,wherein the inflatable member is formed from an insulating material suchthat the inflatable member is configured to direct the electric fieldgenerated by the first and second electrodes toward the wall of thepulmonary vein ostium.
 28. The method of claim 26, further comprisinglocking, after the retracting, a position of the inner shaft relative tothe outer shaft using a locking mechanism of the ablation device. 29.The method of claim 26, further comprising deflecting, prior to theretracting, a portion of the inner shaft to position the inflatablemember in the pulmonary vein ostium.
 30. The method of claim 26, furthercomprising infusing the inflatable member with a fluid.